Tag Archives: Wyss Institute

A 3D printed eye cornea and a 3D printed copy of your brain (also: a Brad Pitt connection)

Sometimes it’s hard to keep up with 3D tissue printing news. I have two news bits, one concerning eyes and another concerning brains.

3D printed human corneas

A May 29, 2018 news item on ScienceDaily trumpets the news,

The first human corneas have been 3D printed by scientists at Newcastle University, UK.

It means the technique could be used in the future to ensure an unlimited supply of corneas.

As the outermost layer of the human eye, the cornea has an important role in focusing vision.

Yet there is a significant shortage of corneas available to transplant, with 10 million people worldwide requiring surgery to prevent corneal blindness as a result of diseases such as trachoma, an infectious eye disorder.

In addition, almost 5 million people suffer total blindness due to corneal scarring caused by burns, lacerations, abrasion or disease.

The proof-of-concept research, published today [May 29, 2018] in Experimental Eye Research, reports how stem cells (human corneal stromal cells) from a healthy donor cornea were mixed together with alginate and collagen to create a solution that could be printed, a ‘bio-ink’.

Here are the proud researchers with their cornea,

Caption: Dr. Steve Swioklo and Professor Che Connon with a dyed cornea. Credit: Newcastle University, UK

A May 30,2018 Newcastle University press release (also on EurekAlert but published on May 29, 2018), which originated the news item, adds more details,

Using a simple low-cost 3D bio-printer, the bio-ink was successfully extruded in concentric circles to form the shape of a human cornea. It took less than 10 minutes to print.

The stem cells were then shown to culture – or grow.

Che Connon, Professor of Tissue Engineering at Newcastle University, who led the work, said: “Many teams across the world have been chasing the ideal bio-ink to make this process feasible.

“Our unique gel – a combination of alginate and collagen – keeps the stem cells alive whilst producing a material which is stiff enough to hold its shape but soft enough to be squeezed out the nozzle of a 3D printer.

“This builds upon our previous work in which we kept cells alive for weeks at room temperature within a similar hydrogel. Now we have a ready to use bio-ink containing stem cells allowing users to start printing tissues without having to worry about growing the cells separately.”

The scientists, including first author and PhD student Ms Abigail Isaacson from the Institute of Genetic Medicine, Newcastle University, also demonstrated that they could build a cornea to match a patient’s unique specifications.

The dimensions of the printed tissue were originally taken from an actual cornea. By scanning a patient’s eye, they could use the data to rapidly print a cornea which matched the size and shape.

Professor Connon added: “Our 3D printed corneas will now have to undergo further testing and it will be several years before we could be in the position where we are using them for transplants.

“However, what we have shown is that it is feasible to print corneas using coordinates taken from a patient eye and that this approach has potential to combat the world-wide shortage.”

Here’s a link to and a citation for the paper,

3D bioprinting of a corneal stroma equivalent by Abigail Isaacson, Stephen Swioklo, Che J. Connon. Experimental Eye Research Volume 173, August 2018, Pages 188–193 and 2018 May 14 pii: S0014-4835(18)30212-4. doi: 10.1016/j.exer.2018.05.010. [Epub ahead of print]

This paper is behind a paywall.

A 3D printed copy of your brain

I love the title for this May 30, 2018 Wyss Institute for Biologically Inspired Engineering news release: Creating piece of mind by Lindsay Brownell (also on EurekAlert),

What if you could hold a physical model of your own brain in your hands, accurate down to its every unique fold? That’s just a normal part of life for Steven Keating, Ph.D., who had a baseball-sized tumor removed from his brain at age 26 while he was a graduate student in the MIT Media Lab’s Mediated Matter group. Curious to see what his brain actually looked like before the tumor was removed, and with the goal of better understanding his diagnosis and treatment options, Keating collected his medical data and began 3D printing his MRI [magnetic resonance imaging] and CT [computed tomography] scans, but was frustrated that existing methods were prohibitively time-intensive, cumbersome, and failed to accurately reveal important features of interest. Keating reached out to some of his group’s collaborators, including members of the Wyss Institute at Harvard University, who were exploring a new method for 3D printing biological samples.

“It never occurred to us to use this approach for human anatomy until Steve came to us and said, ‘Guys, here’s my data, what can we do?” says Ahmed Hosny, who was a Research Fellow with at the Wyss Institute at the time and is now a machine learning engineer at the Dana-Farber Cancer Institute. The result of that impromptu collaboration – which grew to involve James Weaver, Ph.D., Senior Research Scientist at the Wyss Institute; Neri Oxman, [emphasis mine] Ph.D., Director of the MIT Media Lab’s Mediated Matter group and Associate Professor of Media Arts and Sciences; and a team of researchers and physicians at several other academic and medical centers in the US and Germany – is a new technique that allows images from MRI, CT, and other medical scans to be easily and quickly converted into physical models with unprecedented detail. The research is reported in 3D Printing and Additive Manufacturing.

“I nearly jumped out of my chair when I saw what this technology is able to do,” says Beth Ripley, M.D. Ph.D., an Assistant Professor of Radiology at the University of Washington and clinical radiologist at the Seattle VA, and co-author of the paper. “It creates exquisitely detailed 3D-printed medical models with a fraction of the manual labor currently required, making 3D printing more accessible to the medical field as a tool for research and diagnosis.”

Imaging technologies like MRI and CT scans produce high-resolution images as a series of “slices” that reveal the details of structures inside the human body, making them an invaluable resource for evaluating and diagnosing medical conditions. Most 3D printers build physical models in a layer-by-layer process, so feeding them layers of medical images to create a solid structure is an obvious synergy between the two technologies.

However, there is a problem: MRI and CT scans produce images with so much detail that the object(s) of interest need to be isolated from surrounding tissue and converted into surface meshes in order to be printed. This is achieved via either a very time-intensive process called “segmentation” where a radiologist manually traces the desired object on every single image slice (sometimes hundreds of images for a single sample), or an automatic “thresholding” process in which a computer program quickly converts areas that contain grayscale pixels into either solid black or solid white pixels, based on a shade of gray that is chosen to be the threshold between black and white. However, medical imaging data sets often contain objects that are irregularly shaped and lack clear, well-defined borders; as a result, auto-thresholding (or even manual segmentation) often over- or under-exaggerates the size of a feature of interest and washes out critical detail.

The new method described by the paper’s authors gives medical professionals the best of both worlds, offering a fast and highly accurate method for converting complex images into a format that can be easily 3D printed. The key lies in printing with dithered bitmaps, a digital file format in which each pixel of a grayscale image is converted into a series of black and white pixels, and the density of the black pixels is what defines the different shades of gray rather than the pixels themselves varying in color.

Similar to the way images in black-and-white newsprint use varying sizes of black ink dots to convey shading, the more black pixels that are present in a given area, the darker it appears. By simplifying all pixels from various shades of gray into a mixture of black or white pixels, dithered bitmaps allow a 3D printer to print complex medical images using two different materials that preserve all the subtle variations of the original data with much greater accuracy and speed.

The team of researchers used bitmap-based 3D printing to create models of Keating’s brain and tumor that faithfully preserved all of the gradations of detail present in the raw MRI data down to a resolution that is on par with what the human eye can distinguish from about 9-10 inches away. Using this same approach, they were also able to print a variable stiffness model of a human heart valve using different materials for the valve tissue versus the mineral plaques that had formed within the valve, resulting in a model that exhibited mechanical property gradients and provided new insights into the actual effects of the plaques on valve function.

“Our approach not only allows for high levels of detail to be preserved and printed into medical models, but it also saves a tremendous amount of time and money,” says Weaver, who is the corresponding author of the paper. “Manually segmenting a CT scan of a healthy human foot, with all its internal bone structure, bone marrow, tendons, muscles, soft tissue, and skin, for example, can take more than 30 hours, even by a trained professional – we were able to do it in less than an hour.”

The researchers hope that their method will help make 3D printing a more viable tool for routine exams and diagnoses, patient education, and understanding the human body. “Right now, it’s just too expensive for hospitals to employ a team of specialists to go in and hand-segment image data sets for 3D printing, except in extremely high-risk or high-profile cases. We’re hoping to change that,” says Hosny.

In order for that to happen, some entrenched elements of the medical field need to change as well. Most patients’ data are compressed to save space on hospital servers, so it’s often difficult to get the raw MRI or CT scan files needed for high-resolution 3D printing. Additionally, the team’s research was facilitated through a joint collaboration with leading 3D printer manufacturer Stratasys, which allowed access to their 3D printer’s intrinsic bitmap printing capabilities. New software packages also still need to be developed to better leverage these capabilities and make them more accessible to medical professionals.

Despite these hurdles, the researchers are confident that their achievements present a significant value to the medical community. “I imagine that sometime within the next 5 years, the day could come when any patient that goes into a doctor’s office for a routine or non-routine CT or MRI scan will be able to get a 3D-printed model of their patient-specific data within a few days,” says Weaver.

Keating, who has become a passionate advocate of efforts to enable patients to access their own medical data, still 3D prints his MRI scans to see how his skull is healing post-surgery and check on his brain to make sure his tumor isn’t coming back. “The ability to understand what’s happening inside of you, to actually hold it in your hands and see the effects of treatment, is incredibly empowering,” he says.

“Curiosity is one of the biggest drivers of innovation and change for the greater good, especially when it involves exploring questions across disciplines and institutions. The Wyss Institute is proud to be a space where this kind of cross-field innovation can flourish,” says Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS).

Here’s an image illustrating the work,

Caption: This 3D-printed model of Steven Keating’s skull and brain clearly shows his brain tumor and other fine details thanks to the new data processing method pioneered by the study’s authors. Credit: Wyss Institute at Harvard University

Here’s a link to and a citation for the paper,

From Improved Diagnostics to Presurgical Planning: High-Resolution Functionally Graded Multimaterial 3D Printing of Biomedical Tomographic Data Sets by Ahmed Hosny , Steven J. Keating, Joshua D. Dilley, Beth Ripley, Tatiana Kelil, Steve Pieper, Dominik Kolb, Christoph Bader, Anne-Marie Pobloth, Molly Griffin, Reza Nezafat, Georg Duda, Ennio A. Chiocca, James R.. Stone, James S. Michaelson, Mason N. Dean, Neri Oxman, and James C. Weaver. 3D Printing and Additive Manufacturing http://doi.org/10.1089/3dp.2017.0140 Online Ahead of Print:May 29, 2018

This paper appears to be open access.

A tangential Brad Pitt connection

It’s a bit of Hollywood gossip. There was some speculation in April 2018 that Brad Pitt was dating Dr. Neri Oxman highlighted in the Wyss Institute news release. Here’s a sample of an April 13, 2018 posting on Laineygossip (Note: A link has been removed),

It took him a long time to date, but he is now,” the insider tells PEOPLE. “He likes women who challenge him in every way, especially in the intellect department. Brad has seen how happy and different Amal has made his friend (George Clooney). It has given him something to think about.”

While a Pitt source has maintained he and Oxman are “just friends,” they’ve met up a few times since the fall and the insider notes Pitt has been flying frequently to the East Coast. He dropped by one of Oxman’s classes last fall and was spotted at MIT again a few weeks ago.

Pitt and Oxman got to know each other through an architecture project at MIT, where she works as a professor of media arts and sciences at the school’s Media Lab. Pitt has always been interested in architecture and founded the Make It Right Foundation, which builds affordable and environmentally friendly homes in New Orleans for people in need.

“One of the things Brad has said all along is that he wants to do more architecture and design work,” another source says. “He loves this, has found the furniture design and New Orleans developing work fulfilling, and knows he has a talent for it.”

It’s only been a week since Page Six first broke the news that Brad and Dr Oxman have been spending time together.

I’m fascinated by Oxman’s (and her colleagues’) furniture. Rose Brook writes about one particular Oxman piece in her March 27, 2014 posting for TCT magazine (Note: Links have been removed),

MIT Professor and 3D printing forerunner Neri Oxman has unveiled her striking acoustic chaise longue, which was made using Stratasys 3D printing technology.

Oxman collaborated with Professor W Craig Carter and Composer and fellow MIT Professor Tod Machover to explore material properties and their spatial arrangement to form the acoustic piece.

Christened Gemini, the two-part chaise was produced using a Stratasys Objet500 Connex3 multi-colour, multi-material 3D printer as well as traditional furniture-making techniques and it will be on display at the Vocal Vibrations exhibition at Le Laboratoire in Paris from March 28th 2014.

An Architect, Designer and Professor of Media, Arts and Science at MIT, Oxman’s creation aims to convey the relationship of twins in the womb through material properties and their arrangement. It was made using both subtractive and additive manufacturing and is part of Oxman’s ongoing exploration of what Stratasys’ ground-breaking multi-colour, multi-material 3D printer can do.

Brook goes on to explain how the chaise was made and the inspiration that led to it. Finally, it’s interesting to note that Oxman was working with Stratasys in 2014 and that this 2018 brain project is being developed in a joint collaboration with Statasys.

That’s it for 3D printing today.

The Hedy Lamarr of international research: Canada’s Third assessment of The State of Science and Technology and Industrial Research and Development in Canada (1 of 2)

Before launching into the assessment, a brief explanation of my theme: Hedy Lamarr was considered to be one of the great beauties of her day,

“Ziegfeld Girl” Hedy Lamarr 1941 MGM *M.V.
Titles: Ziegfeld Girl
People: Hedy Lamarr
Image courtesy mptvimages.com [downloaded from https://www.imdb.com/title/tt0034415/mediaviewer/rm1566611456]

Aside from starring in Hollywood movies and, before that, movies in Europe, she was also an inventor and not just any inventor (from a Dec. 4, 2017 article by Laura Barnett for The Guardian), Note: Links have been removed,

Let’s take a moment to reflect on the mercurial brilliance of Hedy Lamarr. Not only did the Vienna-born actor flee a loveless marriage to a Nazi arms dealer to secure a seven-year, $3,000-a-week contract with MGM, and become (probably) the first Hollywood star to simulate a female orgasm on screen – she also took time out to invent a device that would eventually revolutionise mobile communications.

As described in unprecedented detail by the American journalist and historian Richard Rhodes in his new book, Hedy’s Folly, Lamarr and her business partner, the composer George Antheil, were awarded a patent in 1942 for a “secret communication system”. It was meant for radio-guided torpedoes, and the pair gave to the US Navy. It languished in their files for decades before eventually becoming a constituent part of GPS, Wi-Fi and Bluetooth technology.

(The article goes on to mention other celebrities [Marlon Brando, Barbara Cartland, Mark Twain, etc] and their inventions.)

Lamarr’s work as an inventor was largely overlooked until the 1990’s when the technology community turned her into a ‘cultish’ favourite and from there her reputation grew and acknowledgement increased culminating in Rhodes’ book and the documentary by Alexandra Dean, ‘Bombshell: The Hedy Lamarr Story (to be broadcast as part of PBS’s American Masters series on May 18, 2018).

Canada as Hedy Lamarr

There are some parallels to be drawn between Canada’s S&T and R&D (science and technology; research and development) and Ms. Lamarr. Chief amongst them, we’re not always appreciated for our brains. Not even by people who are supposed to know better such as the experts on the panel for the ‘Third assessment of The State of Science and Technology and Industrial Research and Development in Canada’ (proper title: Competing in a Global Innovation Economy: The Current State of R&D in Canada) from the Expert Panel on the State of Science and Technology and Industrial Research and Development in Canada.

A little history

Before exploring the comparison to Hedy Lamarr further, here’s a bit more about the history of this latest assessment from the Council of Canadian Academies (CCA), from the report released April 10, 2018,

This assessment of Canada’s performance indicators in science, technology, research, and innovation comes at an opportune time. The Government of Canada has expressed a renewed commitment in several tangible ways to this broad domain of activity including its Innovation and Skills Plan, the announcement of five superclusters, its appointment of a new Chief Science Advisor, and its request for the Fundamental Science Review. More specifically, the 2018 Federal Budget demonstrated the government’s strong commitment to research and innovation with historic investments in science.

The CCA has a decade-long history of conducting evidence-based assessments about Canada’s research and development activities, producing seven assessments of relevance:

The State of Science and Technology in Canada (2006) [emphasis mine]
•Innovation and Business Strategy: Why Canada Falls Short (2009)
•Catalyzing Canada’s Digital Economy (2010)
•Informing Research Choices: Indicators and Judgment (2012)
The State of Science and Technology in Canada (2012) [emphasis mine]
The State of Industrial R&D in Canada (2013) [emphasis mine]
•Paradox Lost: Explaining Canada’s Research Strength and Innovation Weakness (2013)

Using similar methods and metrics to those in The State of Science and Technology in Canada (2012) and The State of Industrial R&D in Canada (2013), this assessment tells a similar and familiar story: Canada has much to be proud of, with world-class researchers in many domains of knowledge, but the rest of the world is not standing still. Our peers are also producing high quality results, and many countries are making significant commitments to supporting research and development that will position them to better leverage their strengths to compete globally. Canada will need to take notice as it determines how best to take action. This assessment provides valuable material for that conversation to occur, whether it takes place in the lab or the legislature, the bench or the boardroom. We also hope it will be used to inform public discussion. [p. ix Print, p. 11 PDF]

This latest assessment succeeds the general 2006 and 2012 reports, which were mostly focused on academic research, and combines it with an assessment of industrial research, which was previously separate. Also, this third assessment’s title (Competing in a Global Innovation Economy: The Current State of R&D in Canada) makes what was previously quietly declared in the text, explicit from the cover onwards. It’s all about competition, despite noises such as the 2017 Naylor report (Review of fundamental research) about the importance of fundamental research.

One other quick comment, I did wonder in my July 1, 2016 posting (featuring the announcement of the third assessment) how combining two assessments would impact the size of the expert panel and the size of the final report,

Given the size of the 2012 assessment of science and technology at 232 pp. (PDF) and the 2013 assessment of industrial research and development at 220 pp. (PDF) with two expert panels, the imagination boggles at the potential size of the 2016 expert panel and of the 2016 assessment combining the two areas.

I got my answer with regard to the panel as noted in my Oct. 20, 2016 update (which featured a list of the members),

A few observations, given the size of the task, this panel is lean. As well, there are three women in a group of 13 (less than 25% representation) in 2016? It’s Ontario and Québec-dominant; only BC and Alberta rate a representative on the panel. I hope they will find ways to better balance this panel and communicate that ‘balanced story’ to the rest of us. On the plus side, the panel has representatives from the humanities, arts, and industry in addition to the expected representatives from the sciences.

The imbalance I noted then was addressed, somewhat, with the selection of the reviewers (from the report released April 10, 2018),

The CCA wishes to thank the following individuals for their review of this report:

Ronald Burnett, C.M., O.B.C., RCA, Chevalier de l’ordre des arts et des
lettres, President and Vice-Chancellor, Emily Carr University of Art and Design
(Vancouver, BC)

Michelle N. Chretien, Director, Centre for Advanced Manufacturing and Design
Technologies, Sheridan College; Former Program and Business Development
Manager, Electronic Materials, Xerox Research Centre of Canada (Brampton,

Lisa Crossley, CEO, Reliq Health Technologies, Inc. (Ancaster, ON)
Natalie Dakers, Founding President and CEO, Accel-Rx Health Sciences
Accelerator (Vancouver, BC)

Fred Gault, Professorial Fellow, United Nations University-MERIT (Maastricht,

Patrick D. Germain, Principal Engineering Specialist, Advanced Aerodynamics,
Bombardier Aerospace (Montréal, QC)

Robert Brian Haynes, O.C., FRSC, FCAHS, Professor Emeritus, DeGroote
School of Medicine, McMaster University (Hamilton, ON)

Susan Holt, Chief, Innovation and Business Relationships, Government of
New Brunswick (Fredericton, NB)

Pierre A. Mohnen, Professor, United Nations University-MERIT and Maastricht
University (Maastricht, Netherlands)

Peter J. M. Nicholson, C.M., Retired; Former and Founding President and
CEO, Council of Canadian Academies (Annapolis Royal, NS)

Raymond G. Siemens, Distinguished Professor, English and Computer Science
and Former Canada Research Chair in Humanities Computing, University of
Victoria (Victoria, BC) [pp. xii- xiv Print; pp. 15-16 PDF]

The proportion of women to men as reviewers jumped up to about 36% (4 of 11 reviewers) and there are two reviewers from the Maritime provinces. As usual, reviewers external to Canada were from Europe. Although this time, they came from Dutch institutions rather than UK or German institutions. Interestingly and unusually, there was no one from a US institution. When will they start using reviewers from other parts of the world?

As for the report itself, it is 244 pp. (PDF). (For the really curious, I have a  December 15, 2016 post featuring my comments on the preliminary data for the third assessment.)

To sum up, they had a lean expert panel tasked with bringing together two inquiries and two reports. I imagine that was daunting. Good on them for finding a way to make it manageable.

Bibliometrics, patents, and a survey

I wish more attention had been paid to some of the issues around open science, open access, and open data, which are changing how science is being conducted. (I have more about this from an April 5, 2018 article by James Somers for The Atlantic but more about that later.) If I understand rightly, they may not have been possible due to the nature of the questions posed by the government when requested the assessment.

As was done for the second assessment, there is an acknowledgement that the standard measures/metrics (bibliometrics [no. of papers published, which journals published them; number of times papers were cited] and technometrics [no. of patent applications, etc.] of scientific accomplishment and progress are not the best and new approaches need to be developed and adopted (from the report released April 10, 2018),

It is also worth noting that the Panel itself recognized the limits that come from using traditional historic metrics. Additional approaches will be needed the next time this assessment is done. [p. ix Print; p. 11 PDF]

For the second assessment and as a means of addressing some of the problems with metrics, the panel decided to take a survey which the panel for the third assessment has also done (from the report released April 10, 2018),

The Panel relied on evidence from multiple sources to address its charge, including a literature review and data extracted from statistical agencies and organizations such as Statistics Canada and the OECD. For international comparisons, the Panel focused on OECD countries along with developing countries that are among the top 20 producers of peer-reviewed research publications (e.g., China, India, Brazil, Iran, Turkey). In addition to the literature review, two primary research approaches informed the Panel’s assessment:
•a comprehensive bibliometric and technometric analysis of Canadian research publications and patents; and,
•a survey of top-cited researchers around the world.

Despite best efforts to collect and analyze up-to-date information, one of the Panel’s findings is that data limitations continue to constrain the assessment of R&D activity and excellence in Canada. This is particularly the case with industrial R&D and in the social sciences, arts, and humanities. Data on industrial R&D activity continue to suffer from time lags for some measures, such as internationally comparable data on R&D intensity by sector and industry. These data also rely on industrial categories (i.e., NAICS and ISIC codes) that can obscure important trends, particularly in the services sector, though Statistics Canada’s recent revisions to how this data is reported have improved this situation. There is also a lack of internationally comparable metrics relating to R&D outcomes and impacts, aside from those based on patents.

For the social sciences, arts, and humanities, metrics based on journal articles and other indexed publications provide an incomplete and uneven picture of research contributions. The expansion of bibliometric databases and methodological improvements such as greater use of web-based metrics, including paper views/downloads and social media references, will support ongoing, incremental improvements in the availability and accuracy of data. However, future assessments of R&D in Canada may benefit from more substantive integration of expert review, capable of factoring in different types of research outputs (e.g., non-indexed books) and impacts (e.g., contributions to communities or impacts on public policy). The Panel has no doubt that contributions from the humanities, arts, and social sciences are of equal importance to national prosperity. It is vital that such contributions are better measured and assessed. [p. xvii Print; p. 19 PDF]

My reading: there’s a problem and we’re not going to try and fix it this time. Good luck to those who come after us. As for this line: “The Panel has no doubt that contributions from the humanities, arts, and social sciences are of equal importance to national prosperity.” Did no one explain that when you use ‘no doubt’, you are introducing doubt? It’s a cousin to ‘don’t take this the wrong way’ and ‘I don’t mean to be rude but …’ .

Good news

This is somewhat encouraging (from the report released April 10, 2018),

Canada’s international reputation for its capacity to participate in cutting-edge R&D is strong, with 60% of top-cited researchers surveyed internationally indicating that Canada hosts world-leading infrastructure or programs in their fields. This share increased by four percentage points between 2012 and 2017. Canada continues to benefit from a highly educated population and deep pools of research skills and talent. Its population has the highest level of educational attainment in the OECD in the proportion of the population with
a post-secondary education. However, among younger cohorts (aged 25 to 34), Canada has fallen behind Japan and South Korea. The number of researchers per capita in Canada is on a par with that of other developed countries, andincreased modestly between 2004 and 2012. Canada’s output of PhD graduates has also grown in recent years, though it remains low in per capita terms relative to many OECD countries. [pp. xvii-xviii; pp. 19-20]

Don’t let your head get too big

Most of the report observes that our international standing is slipping in various ways such as this (from the report released April 10, 2018),

In contrast, the number of R&D personnel employed in Canadian businesses
dropped by 20% between 2008 and 2013. This is likely related to sustained and
ongoing decline in business R&D investment across the country. R&D as a share
of gross domestic product (GDP) has steadily declined in Canada since 2001,
and now stands well below the OECD average (Figure 1). As one of few OECD
countries with virtually no growth in total national R&D expenditures between
2006 and 2015, Canada would now need to more than double expenditures to
achieve an R&D intensity comparable to that of leading countries.

Low and declining business R&D expenditures are the dominant driver of this
trend; however, R&D spending in all sectors is implicated. Government R&D
expenditures declined, in real terms, over the same period. Expenditures in the
higher education sector (an indicator on which Canada has traditionally ranked
highly) are also increasing more slowly than the OECD average. Significant
erosion of Canada’s international competitiveness and capacity to participate
in R&D and innovation is likely to occur if this decline and underinvestment

Between 2009 and 2014, Canada produced 3.8% of the world’s research
publications, ranking ninth in the world. This is down from seventh place for
the 2003–2008 period. India and Italy have overtaken Canada although the
difference between Italy and Canada is small. Publication output in Canada grew
by 26% between 2003 and 2014, a growth rate greater than many developed
countries (including United States, France, Germany, United Kingdom, and
Japan), but below the world average, which reflects the rapid growth in China
and other emerging economies. Research output from the federal government,
particularly the National Research Council Canada, dropped significantly
between 2009 and 2014.(emphasis mine)  [p. xviii Print; p. 20 PDF]

For anyone unfamiliar with Canadian politics,  2009 – 2014 were years during which Stephen Harper’s Conservatives formed the government. Justin Trudeau’s Liberals were elected to form the government in late 2015.

During Harper’s years in government, the Conservatives were very interested in changing how the National Research Council of Canada operated and, if memory serves, the focus was on innovation over research. Consequently, the drop in their research output is predictable.

Given my interest in nanotechnology and other emerging technologies, this popped out (from the report released April 10, 2018),

When it comes to research on most enabling and strategic technologies, however, Canada lags other countries. Bibliometric evidence suggests that, with the exception of selected subfields in Information and Communication Technologies (ICT) such as Medical Informatics and Personalized Medicine, Canada accounts for a relatively small share of the world’s research output for promising areas of technology development. This is particularly true for Biotechnology, Nanotechnology, and Materials science [emphasis mine]. Canada’s research impact, as reflected by citations, is also modest in these areas. Aside from Biotechnology, none of the other subfields in Enabling and Strategic Technologies has an ARC rank among the top five countries. Optoelectronics and photonics is the next highest ranked at 7th place, followed by Materials, and Nanoscience and Nanotechnology, both of which have a rank of 9th. Even in areas where Canadian researchers and institutions played a seminal role in early research (and retain a substantial research capacity), such as Artificial Intelligence and Regenerative Medicine, Canada has lost ground to other countries.

Arguably, our early efforts in artificial intelligence wouldn’t have garnered us much in the way of ranking and yet we managed some cutting edge work such as machine learning. I’m not suggesting the expert panel should have or could have found some way to measure these kinds of efforts but I’m wondering if there could have been some acknowledgement in the text of the report. I’m thinking a couple of sentences in a paragraph about the confounding nature of scientific research where areas that are ignored for years and even decades then become important (e.g., machine learning) but are not measured as part of scientific progress until after they are universally recognized.

Still, point taken about our diminishing returns in ’emerging’ technologies and sciences (from the report released April 10, 2018),

The impression that emerges from these data is sobering. With the exception of selected ICT subfields, such as Medical Informatics, bibliometric evidence does not suggest that Canada excels internationally in most of these research areas. In areas such as Nanotechnology and Materials science, Canada lags behind other countries in levels of research output and impact, and other countries are outpacing Canada’s publication growth in these areas — leading to declining shares of world publications. Even in research areas such as AI, where Canadian researchers and institutions played a foundational role, Canadian R&D activity is not keeping pace with that of other countries and some researchers trained in Canada have relocated to other countries (Section 4.4.1). There are isolated exceptions to these trends, but the aggregate data reviewed by this Panel suggest that Canada is not currently a world leader in research on most emerging technologies.

The Hedy Lamarr treatment

We have ‘good looks’ (arts and humanities) but not the kind of brains (physical sciences and engineering) that people admire (from the report released April 10, 2018),

Canada, relative to the world, specializes in subjects generally referred to as the
humanities and social sciences (plus health and the environment), and does
not specialize as much as others in areas traditionally referred to as the physical
sciences and engineering. Specifically, Canada has comparatively high levels
of research output in Psychology and Cognitive Sciences, Public Health and
Health Services, Philosophy and Theology, Earth and Environmental Sciences,
and Visual and Performing Arts. [emphases mine] It accounts for more than 5% of world researchin these fields. Conversely, Canada has lower research output than expected
in Chemistry, Physics and Astronomy, Enabling and Strategic Technologies,
Engineering, and Mathematics and Statistics. The comparatively low research
output in core areas of the natural sciences and engineering is concerning,
and could impair the flexibility of Canada’s research base, preventing research
institutions and researchers from being able to pivot to tomorrow’s emerging
research areas. [p. xix Print; p. 21 PDF]

Couldn’t they have used a more buoyant tone? After all, science was known as ‘natural philosophy’ up until the 19th century. As for visual and performing arts, let’s include poetry as a performing and literary art (both have been the case historically and cross-culturally) and let’s also note that one of the great physics texts, (De rerum natura by Lucretius) was a multi-volume poem (from Lucretius’ Wikipedia entry; Note: Links have been removed).

His poem De rerum natura (usually translated as “On the Nature of Things” or “On the Nature of the Universe”) transmits the ideas of Epicureanism, which includes Atomism [the concept of atoms forming materials] and psychology. Lucretius was the first writer to introduce Roman readers to Epicurean philosophy.[15] The poem, written in some 7,400 dactylic hexameters, is divided into six untitled books, and explores Epicurean physics through richly poetic language and metaphors. Lucretius presents the principles of atomism; the nature of the mind and soul; explanations of sensation and thought; the development of the world and its phenomena; and explains a variety of celestial and terrestrial phenomena. The universe described in the poem operates according to these physical principles, guided by fortuna, “chance”, and not the divine intervention of the traditional Roman deities.[16]

Should you need more proof that the arts might have something to contribute to physical sciences, there’s this in my March 7, 2018 posting,

It’s not often you see research that combines biologically inspired engineering and a molecular biophysicist with a professional animator who worked at Peter Jackson’s (Lord of the Rings film trilogy, etc.) Park Road Post film studio. An Oct. 18, 2017 news item on ScienceDaily describes the project,

Like many other scientists, Don Ingber, M.D., Ph.D., the Founding Director of the Wyss Institute, [emphasis mine] is concerned that non-scientists have become skeptical and even fearful of his field at a time when technology can offer solutions to many of the world’s greatest problems. “I feel that there’s a huge disconnect between science and the public because it’s depicted as rote memorization in schools, when by definition, if you can memorize it, it’s not science,” says Ingber, who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children’s Hospital, and Professor of Bioengineering at the Harvard Paulson School of Engineering and Applied Sciences (SEAS). [emphasis mine] “Science is the pursuit of the unknown. We have a responsibility to reach out to the public and convey that excitement of exploration and discovery, and fortunately, the film industry is already great at doing that.”

“Not only is our physics-based simulation and animation system as good as other data-based modeling systems, it led to the new scientific insight [emphasis mine] that the limited motion of the dynein hinge focuses the energy released by ATP hydrolysis, which causes dynein’s shape change and drives microtubule sliding and axoneme motion,” says Ingber. “Additionally, while previous studies of dynein have revealed the molecule’s two different static conformations, our animation visually depicts one plausible way that the protein can transition between those shapes at atomic resolution, which is something that other simulations can’t do. The animation approach also allows us to visualize how rows of dyneins work in unison, like rowers pulling together in a boat, which is difficult using conventional scientific simulation approaches.”

It comes down to how we look at things. Yes, physical sciences and engineering are very important. If the report is to be believed we have a very highly educated population and according to PISA scores our students rank highly in mathematics, science, and reading skills. (For more information on Canada’s latest PISA scores from 2015 see this OECD page. As for PISA itself, it’s an OECD [Organization for Economic Cooperation and Development] programme where 15-year-old students from around the world are tested on their reading, mathematics, and science skills, you can get some information from my Oct. 9, 2013 posting.)

Is it really so bad that we choose to apply those skills in fields other than the physical sciences and engineering? It’s a little bit like Hedy Lamarr’s problem except instead of being judged for our looks and having our inventions dismissed, we’re being judged for not applying ourselves to physical sciences and engineering and having our work in other closely aligned fields dismissed as less important.

Canada’s Industrial R&D: an oft-told, very sad story

Bemoaning the state of Canada’s industrial research and development efforts has been a national pastime as long as I can remember. Here’s this from the report released April 10, 2018,

There has been a sustained erosion in Canada’s industrial R&D capacity and competitiveness. Canada ranks 33rd among leading countries on an index assessing the magnitude, intensity, and growth of industrial R&D expenditures. Although Canada is the 11th largest spender, its industrial R&D intensity (0.9%) is only half the OECD average and total spending is declining (−0.7%). Compared with G7 countries, the Canadian portfolio of R&D investment is more concentrated in industries that are intrinsically not as R&D intensive. Canada invests more heavily than the G7 average in oil and gas, forestry, machinery and equipment, and finance where R&D has been less central to business strategy than in many other industries. …  About 50% of Canada’s industrial R&D spending is in high-tech sectors (including industries such as ICT, aerospace, pharmaceuticals, and automotive) compared with the G7 average of 80%. Canadian Business Enterprise Expenditures on R&D (BERD) intensity is also below the OECD average in these sectors. In contrast, Canadian investment in low and medium-low tech sectors is substantially higher than the G7 average. Canada’s spending reflects both its long-standing industrial structure and patterns of economic activity.

R&D investment patterns in Canada appear to be evolving in response to global and domestic shifts. While small and medium-sized enterprises continue to perform a greater share of industrial R&D in Canada than in the United States, between 2009 and 2013, there was a shift in R&D from smaller to larger firms. Canada is an increasingly attractive place to conduct R&D. Investment by foreign-controlled firms in Canada has increased to more than 35% of total R&D investment, with the United States accounting for more than half of that. [emphasis mine]  Multinational enterprises seem to be increasingly locating some of their R&D operations outside their country of ownership, possibly to gain proximity to superior talent. Increasing foreign-controlled R&D, however, also could signal a long-term strategic loss of control over intellectual property (IP) developed in this country, ultimately undermining the government’s efforts to support high-growth firms as they scale up. [pp. xxii-xxiii Print; pp. 24-25 PDF]

Canada has been known as a ‘branch plant’ economy for decades. For anyone unfamiliar with the term, it means that companies from other countries come here, open up a branch and that’s how we get our jobs as we don’t have all that many large companies here. Increasingly, multinationals are locating R&D shops here.

While our small to medium size companies fund industrial R&D, it’s large companies (multinationals) which can afford long-term and serious investment in R&D. Luckily for companies from other countries, we have a well-educated population of people looking for jobs.

In 2017, we opened the door more widely so we can scoop up talented researchers and scientists from other countries, from a June 14, 2017 article by Beckie Smith for The PIE News,

Universities have welcomed the inclusion of the work permit exemption for academic stays of up to 120 days in the strategy, which also introduces expedited visa processing for some highly skilled professions.

Foreign researchers working on projects at a publicly funded degree-granting institution or affiliated research institution will be eligible for one 120-day stay in Canada every 12 months.

And universities will also be able to access a dedicated service channel that will support employers and provide guidance on visa applications for foreign talent.

The Global Skills Strategy, which came into force on June 12 [2017], aims to boost the Canadian economy by filling skills gaps with international talent.

As well as the short term work permit exemption, the Global Skills Strategy aims to make it easier for employers to recruit highly skilled workers in certain fields such as computer engineering.

“Employers that are making plans for job-creating investments in Canada will often need an experienced leader, dynamic researcher or an innovator with unique skills not readily available in Canada to make that investment happen,” said Ahmed Hussen, Minister of Immigration, Refugees and Citizenship.

“The Global Skills Strategy aims to give those employers confidence that when they need to hire from abroad, they’ll have faster, more reliable access to top talent.”

Coincidentally, Microsoft, Facebook, Google, etc. have announced, in 2017, new jobs and new offices in Canadian cities. There’s a also Chinese multinational telecom company Huawei Canada which has enjoyed success in Canada and continues to invest here (from a Jan. 19, 2018 article about security concerns by Matthew Braga for the Canadian Broadcasting Corporation (CBC) online news,

For the past decade, Chinese tech company Huawei has found no shortage of success in Canada. Its equipment is used in telecommunications infrastructure run by the country’s major carriers, and some have sold Huawei’s phones.

The company has struck up partnerships with Canadian universities, and say it is investing more than half a billion dollars in researching next generation cellular networks here. [emphasis mine]

While I’m not thrilled about using patents as an indicator of progress, this is interesting to note (from the report released April 10, 2018),

Canada produces about 1% of global patents, ranking 18th in the world. It lags further behind in trademark (34th) and design applications (34th). Despite relatively weak performance overall in patents, Canada excels in some technical fields such as Civil Engineering, Digital Communication, Other Special Machines, Computer Technology, and Telecommunications. [emphases mine] Canada is a net exporter of patents, which signals the R&D strength of some technology industries. It may also reflect increasing R&D investment by foreign-controlled firms. [emphasis mine] [p. xxiii Print; p. 25 PDF]

Getting back to my point, we don’t have large companies here. In fact, the dream for most of our high tech startups is to build up the company so it’s attractive to buyers, sell, and retire (hopefully before the age of 40). Strangely, the expert panel doesn’t seem to share my insight into this matter,

Canada’s combination of high performance in measures of research output and impact, and low performance on measures of industrial R&D investment and innovation (e.g., subpar productivity growth), continue to be viewed as a paradox, leading to the hypothesis that barriers are impeding the flow of Canada’s research achievements into commercial applications. The Panel’s analysis suggests the need for a more nuanced view. The process of transforming research into innovation and wealth creation is a complex multifaceted process, making it difficult to point to any definitive cause of Canada’s deficit in R&D investment and productivity growth. Based on the Panel’s interpretation of the evidence, Canada is a highly innovative nation, but significant barriers prevent the translation of innovation into wealth creation. The available evidence does point to a number of important contributing factors that are analyzed in this report. Figure 5 represents the relationships between R&D, innovation, and wealth creation.

The Panel concluded that many factors commonly identified as points of concern do not adequately explain the overall weakness in Canada’s innovation performance compared with other countries. [emphasis mine] Academia-business linkages appear relatively robust in quantitative terms given the extent of cross-sectoral R&D funding and increasing academia-industry partnerships, though the volume of academia-industry interactions does not indicate the nature or the quality of that interaction, nor the extent to which firms are capitalizing on the research conducted and the resulting IP. The educational system is high performing by international standards and there does not appear to be a widespread lack of researchers or STEM (science, technology, engineering, and mathematics) skills. IP policies differ across universities and are unlikely to explain a divergence in research commercialization activity between Canadian and U.S. institutions, though Canadian universities and governments could do more to help Canadian firms access university IP and compete in IP management and strategy. Venture capital availability in Canada has improved dramatically in recent years and is now competitive internationally, though still overshadowed by Silicon Valley. Technology start-ups and start-up ecosystems are also flourishing in many sectors and regions, demonstrating their ability to build on research advances to develop and deliver innovative products and services.

You’ll note there’s no mention of a cultural issue where start-ups are designed for sale as soon as possible and this isn’t new. Years ago, there was an accounting firm that published a series of historical maps (the last one I saw was in 2005) of technology companies in the Vancouver region. Technology companies were being developed and sold to large foreign companies from the 19th century to present day.

Part 2

Art influences science

It’s not often you see research that combines biologically inspired engineering and a molecular biophysicist with a professional animator who worked at Peter Jackson’s (Lord of the Rings film trilogy, etc.) Park Road Post film studio. An Oct. 18, 2017 news item on ScienceDaily describes the project,

Like many other scientists, Don Ingber, M.D., Ph.D., the Founding Director of the Wyss Institute, is concerned that non-scientists have become skeptical and even fearful of his field at a time when technology can offer solutions to many of the world’s greatest problems. “I feel that there’s a huge disconnect between science and the public because it’s depicted as rote memorization in schools, when by definition, if you can memorize it, it’s not science,” says Ingber, who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children’s Hospital, and Professor of Bioengineering at the Harvard Paulson School of Engineering and Applied Sciences (SEAS). “Science is the pursuit of the unknown. We have a responsibility to reach out to the public and convey that excitement of exploration and discovery, and fortunately, the film industry is already great at doing that.”

An October 18, 2017 Wyss Institute at Harvard University news release (also on EurekAlert) by Lindsay Brownell, which originated the news item, details the work,

To see if entertainment could offer a solution to this challenge, Ingber teamed up with Charles Reilly, Ph.D., a molecular biophysicist, professional animator, and Staff Scientist at the Wyss Institute who previously worked at movie director Peter Jackson’s Park Road Post film studio, to create a film that would capture viewers’ imaginations by telling the story of a biological process that was accurate down to the atomic level. “Don and I quickly found that we have a lot of things in common, especially that we’re both systems thinkers,” says Reilly. “Applying an artistic process to science frees you from the typically reductionist approach of analyzing one particular hypothesis and teaches you a different way of observing things. As a result, we not only created an entertaining tool for public outreach, we conducted robust theoretical biology research that led to new scientific insight into molecular-scale processes.” The research is now published in ACS Nano and the film can be found here.

Wyss researchers created a model of an axoneme that displays how different segments of the microtubules bend and flex relative to each other to create movement. Credit: Wyss Institute at Harvard University

Any good movie needs characters and drama, and a “hook” to get the audience invested in watching. The scientists decided to make a parody of a trailer for a Star Wars® movie, but instead of showing starship cruisers hurtling through space towards the Death Star, they chose a biological process with its own built-in narrative: the fertilization of an egg by a sperm, in which millions of sperm race to be the one that succeeds and creates the next generation of life. The patterns and mechanics of sperm swimming have been studied and described in scientific literature, but visually showing the accurate movement of a sperm tail required tackling one of the toughest challenges facing science today: how to create a multi-scale biological model that maintains accuracy at different sizes, from cells all the way down to atoms. That would be like starting with the Empire State Building and then zooming in close enough to see every individual screw, nut and bolt that holds it together, as well as how individual water molecules flow inside its pipes, while maintaining crystal-clear resolution – not an easy task.

“It turns out that creating an accurate biological model and creating a believable computer-generated depiction of life in film are very similar, in that you’re constantly troubleshooting and modifying your virtual object until it fits the way things actually look and move,” says Reilly. “However, for biology, the simulations also have to align with recorded scientific data and theoretical models that have previously been experimentally validated.” The scientists created a design-based animation pipeline that integrates physics-based film animation software with molecular dynamics simulation software to create a model of how a sperm tail moves based on scientific data, with the criterion that the model had to work across all size scales. “This is really a design thinking approach, where you have to be willing to throw out your model if it doesn’t work correctly when you integrate it with data from another scale,” Reilly says. “A lot of scientific investigations use a reductionist approach, focusing on one molecule or one biological system with higher and higher resolution without placing it in context, which makes it difficult to converge on a picture of the larger whole.”

This video shows dynein’s two different shapes as determined from scientific observations, and how the Wyss researchers’ molecular model of dynein’s movement fits those conformations. Credit: Wyss Institute at Harvard University

The core of a sperm’s whip-like tail is the axoneme, a long tube consisting of nine pairs of microtubules arranged in a column around a central pair, all of which extend the entire length of the tail. The axoneme’s rhythmic bending and stretching is the source of the tail’s movement, and the scientists knew they needed to realistically depict that process in order to show the film’s viewers how a sperm moves. Rather than construct a model in a linear fashion by “zooming in” or “zooming out” to add more information to a single starting structure, they built the model at different scales simultaneously, repeatedly checking it against scientific data to ensure it was accurate and modifying it until the pieces fit together.

The axoneme’s movement is accomplished via rows of motor proteins called dyneins that are attached along the microtubules and exert force on them so the microtubules “slide” past each other, which then causes the entire axoneme and sperm tail to bend and move. The dynein protein has a long “arm” portion that grabs onto the neighboring microtubule and, when the protein changes from one shape to another, pulls the microtubule along with it. Dynein switches between these different conformations as a result of the conversion of a molecule of ATP to ADP at a specific binding site on the protein, which releases energy as a chemical bond is broken. To model this molecular motor, the scientists created a molecular dynamics simulation of a dynein protein and applied energy at the ATP binding site to approximate the transfer of energy from ATP. They found that this caused atoms in the entire protein to move in random directions when they performed their simulation of dynein floating in solution, as most conventional scientific simulations do. However, when they then “fixed” a specific hinge region of the dynein molecule that is known to connect dynein to its microtubule, they discovered that the dynein spontaneously moved in its characteristic direction when force was applied at the ATP binding site, matching the way it moves in nature.

This video shows rows of dynein proteins along the microtubules of an axoneme moving in sync to cause the axoneme’s motion, like rowers pulling synchronously in a boat. Credit: Wyss Institute at Harvard University

“Not only is our physics-based simulation and animation system as good as other data-based modeling systems, it led to the new scientific insight that the limited motion of the dynein hinge focuses the energy released by ATP hydrolysis, which causes dynein’s shape change and drives microtubule sliding and axoneme motion,” says Ingber. “Additionally, while previous studies of dynein have revealed the molecule’s two different static conformations, our animation visually depicts one plausible way that the protein can transition between those shapes at atomic resolution, which is something that other simulations can’t do. The animation approach also allows us to visualize how rows of dyneins work in unison, like rowers pulling together in a boat, which is difficult using conventional scientific simulation approaches.”

Using this biologically accurate model of how dynein moves the microtubules within the axoneme, Ingber and Reilly created a short film called “The Beginning,” which draws parallels between sperm swimming toward an egg and spaceships flying toward a planet in space, giving an artistic bent to a scientific topic. The film depicts several sperm attempting to fertilize the egg, “zooms in” on one sperm’s tail to show how the dynein proteins move in sync to cause the tail to bend and flex, and ends with the sperm’s successful journey into the egg and the initiation of cell division that will ultimately create a new organism. The scientists submitted the film along with the paper to several academic journals, and it took a long time before they found an open-minded editor who recognized that the paper and film together were a powerful demonstration of how starting with an artistic goal can end up generating new scientific discoveries along with a tool for public outreach.

*Due to distortion images deleted March 9, 2018.*

“Both science and art are about observation, interpretation, and communication. Our goal is that presenting science to the public in an entertaining, system-based way, rather than bogging them down with a series of scattered facts, will help more people understand it and feel that they can contribute to the scientific conversation. The more people engage with science, the more likely humanity is to solve the world’s big problems,” says Reilly. “I also hope that this paper and video encourage more scientists to take an artistic approach when they start a new project, not necessarily to create a narrative-based story, but to explore their idea the way an artist explores a canvas, because that makes the mind open to a different form of serendipity that can lead to unexpected results.”

“The Wyss Institute is driven by biological design. In this project, we used design tools and approaches borrowed from the art world to solve problems related to motion, form, and complexity to create something entertaining, which ultimately led to new scientific insights and, hopefully, new ways to excite the public about science,” says Ingber. “We’ve demonstrated that art and science can benefit each other in a truly reciprocal way, and we hope that this project spurs future collaborations with the entertainment industry so that both art and science can get even closer to depicting reality in ways that anyone can appreciate and enjoy.”

*Due to distortion images deleted on March 9, 2018.*

The film,

Here’s a link to and a citation for the paper,

Art Advancing Science: Filmmaking Leads to Molecular Insights at the Nanoscale by Charles Reilly and Donald E. Ingber. ACS Nano, Article ASAP DOI: 10.1021/acsnano.7b05266 Publication Date (Web): October 18, 2017

Copyright © 2017 American Chemical Society

This paper appears to be open access.

Getting up to the size of a dust speck, the first ‘large’ self-assembling DNA crystals

An Oct. 19, 2014 news item on ScienceDaily describes the latest developments in ‘DNA nanotechnology’ research at the Wyss Institute for Biologically Inspired Engineering at Harvard University,

DNA has garnered attention for its potential as a programmable material platform that could spawn entire new and revolutionary nanodevices in computer science, microscopy, biology, and more. Researchers have been working to master the ability to coax DNA molecules to self assemble into the precise shapes and sizes needed in order to fully realize these nanotechnology dreams.

For the last 20 years, scientists have tried to design large DNA crystals with precisely prescribed depth and complex features — a design quest just fulfilled by a team at Harvard’s Wyss Institute for Biologically Inspired Engineering. The team built 32 DNA crystals with precisely-defined depth and an assortment of sophisticated three-dimensional (3D) features, an advance reported in Nature Chemistry.

It seems a bit of a misleading for the Wyss Institute to state the ‘team built’ the DNA crystals as they are self-assembling according to this Oct. 19, 2014 Wyss Institute news release (also on EurekAlert), which originated the news item,

The team used their “DNA-brick self-assembly” method, which was first unveiled in a 2012 Science publication when they created more than 100 3D complex nanostructures about the size of viruses. The newly-achieved periodic crystal structures are more than 1000 times larger than those discrete DNA brick structures, sizing up closer to a speck of dust, which is actually quite large in the world of DNA nanotechnology.

“We are very pleased that our DNA brick approach has solved this challenge,” said senior author and Wyss Institute Core Faculty member Peng Yin, Ph.D., who is also an Associate Professor of Systems Biology at Harvard Medical School, “and we were actually surprised by how well it works.”

The news release goes on to describe some of the issues with other self-assembly methods along with more details about the ‘DNA brick’ approach,

Scientists have struggled to crystallize complex 3D DNA nanostructures using more conventional self-assembly methods. The risk of error tends to increase with the complexity of the structural repeating units and the size of the DNA crystal to be assembled.

The DNA brick method uses short, synthetic strands of DNA that work like interlocking Lego® bricks to build complex structures. Structures are first designed using a computer model of a molecular cube, which becomes a master canvas. Each brick is added or removed independently from the 3D master canvas to arrive at the desired shape – and then the design is put into action: the DNA strands that would match up to achieve the desired structure are mixed together and self assemble to achieve the designed crystal structures.

“Therein lies the key distinguishing feature of our design strategy—its modularity,” said co-lead author Yonggang Ke, Ph.D., formerly a Wyss Institute Postdoctoral Fellow and now an assistant professor at the Georgia Institute of Technology and Emory University. “The ability to simply add or remove pieces from the master canvas makes it easy to create virtually any design.”

The modularity also makes it relatively easy to precisely define the crystal depth. “This is the first time anyone has demonstrated the ability to rationally design crystal depth with nanometer precision, up to 80 nm in this study,” Ke said. In contrast, previous two-dimensional DNA lattices are typically single-layer structures with only 2 nm depth.

“DNA crystals are attractive for nanotechnology applications because they are comprised of repeating structural units that provide an ideal template for scalable design features”, said co-lead author graduate student Luvena Ong.

Furthermore, as part of this study the team demonstrated the ability to position gold nanoparticles into prescribed 2D architectures less than two nanometers apart from each other along the crystal structure – a critical feature for future quantum devices and a significant technical advance for their scalable production, said co-lead author Wei Sun, Ph.D., Wyss Institute Postdoctoral Fellow.

“My preconceived notions of the limitations of DNA have been consistently shattered by our new advances in DNA nanotechnology,” said William Shih, Ph.D., who is co-author of the study and a Wyss Institute Founding Core Faculty member, as well as Associate Professor in the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School and the Department of Cancer Biology at the Dana-Farber Cancer Institute. “DNA nanotechnology now makes it possible for us to assemble, in a programmable way, prescribed structures rivaling the complexity of many molecular machines we see in Nature.”

“Peng’s team is using the DNA-brick self-assembly method to build the foundation for the new landscape of DNA nanotechnology at an impressive pace,” said Wyss Institute Founding Director Don Ingber, M.D., Ph.D. “What have been mere visions of how the DNA molecule could be used to advance everything from the semiconductor industry to biophysics are fast becoming realities.”

Here’s a link to and a citation for the latest paper,

DNA brick crystals with prescribed depths by Yonggang Ke, Luvena L. Ong, Wei Sun, Jie Song, Mingdong Dong, William M. Shih, & Peng Yin. Nature Chemistry (2014) doi:10.1038/nchem.2083 Published online 19 October 2014

This paper is behind a paywall.

SLIPS (Slippery Liquid-Infused Porous Surfaces) technology repels blood and bacteria from medical devices

Researchers at Harvard University’s Wyss Institute for Biologically Inspired Engineering have developed a coating for medical devices that helps to address some of these devices’ most  troublesome aspects. From an Oct. 12, 2014 news item on ScienceDaily,

From joint replacements to cardiac implants and dialysis machines, medical devices enhance or save lives on a daily basis. However, any device implanted in the body or in contact with flowing blood faces two critical challenges that can threaten the life of the patient the device is meant to help: blood clotting and bacterial infection.

A team of Harvard scientists and engineers may have a solution. They developed a new surface coating for medical devices using materials already approved by the Food and Drug Administration (FDA). The coating repelled blood from more than 20 medically relevant substrates the team tested — made of plastic to glass and metal — and also suppressed biofilm formation in a study reported in Nature Biotechnology. But that’s not all.

The team implanted medical-grade tubing and catheters coated with the material in large blood vessels in pigs, and it prevented blood from clotting for at least eight hours without the use of blood thinners such as heparin. Heparin is notorious for causing potentially lethal side-effects like excessive bleeding but is often a necessary evil in medical treatments where clotting is a risk.

“Devising a way to prevent blood clotting without using anticoagulants is one of the holy grails in medicine,” said Don Ingber, M.D., Ph.D., Founding Director of Harvard’s Wyss Institute for Biologically Inspired Engineering and senior author of the study. Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, as well as professor of bioengineering at Harvard School of Engineering and Applied Sciences (SEAS).

An Oct. 12, 2014 Wyss Institute news release (also on EurekAlert), which originated the news item, describes the inspiration for this work,

The idea for the coating evolved from SLIPS, a pioneering surface technology developed by coauthor Joanna Aizenberg, Ph.D., who is a Wyss Institute Core Faculty member and the Amy Smith Berylson Professor of Materials Science at Harvard SEAS. SLIPS stands for Slippery Liquid-Infused Porous Surfaces. Inspired by the slippery surface of the carnivorous pitcher plant, which enables the plant to capture insects, SLIPS repels nearly any material it contacts. The liquid layer on the surface provides a barrier to everything from ice to crude oil and blood.

“Traditional SLIPS uses porous, textured surface substrates to immobilize the liquid layer whereas medical surfaces are mostly flat and smooth – so we further adapted our approach by capitalizing on the natural roughness of chemically modified surfaces of medical devices,” said Aizenberg, who leads the Wyss Institute’s Adaptive Materials platform. “This is yet another incarnation of the highly customizable SLIPS platform that can be designed to create slippery, non-adhesive surfaces on any material.”

The Wyss team developed a super-repellent coating that can be adhered to existing, approved medical devices. In a two-step surface-coating process, they chemically attached a monolayer of perfluorocarbon, which is similar to Teflon. Then they added a layer of liquid perfluorocarbon, which is widely used in medicine for applications such as liquid ventilation for infants with breathing challenges, blood substitution, eye surgery, and more. The team calls the tethered perfluorocarbon plus the liquid layer a Tethered-Liquid Perfluorocarbon surface, or TLP for short.

In addition to working seamlessly when coated on more than 20 different medical surfaces and lasting for more than eight hours to prevent clots in a pig under relatively high blood flow rates without the use of heparin, the TLP coating achieved the following results:

  • TLP-treated medical tubing was stored for more than a year under normal temperature and humidity conditions and still prevented clot formation
  • The TLP surface remained stable under the full range of clinically relevant physiological shear stresses, or rates of blood flow seen in catheters and central lines, all the way up to dialysis machines
  • It repelled the components of blood that cause clotting (fibrin and platelets)
  • When bacteria called Pseudomonas aeruginosa were grown in TLP-coated medical tubing for more than six weeks, less than one in a billion bacteria were able to adhere. Central lines coated with TLP significantly reduce sepsis from Central-Line Mediated Bloodstream Infections (CLABSI). (Sepsis is a life-threatening blood infection caused by bacteria, and a significant risk for patients with implanted medical devices.)

Out of sheer curiosity, the researchers even tested a TLP-coated surface with a gecko – the superstar of sticking whose footpads contain many thousands of hairlike structures with tremendous adhesive strength. The gecko was unable to hold on.

“We were wonderfully surprised by how well the TLP coating worked, particularly in vivo without heparin,” said one of the co-lead authors, Anna Waterhouse, Ph.D., a Wyss Institute Postdoctoral Fellow. “Usually the blood will start to clot within an hour in the extracorporeal circuit, so our experiments really demonstrate the clinical relevance of this new coating.”

While most of the team’s demonstrations were performed on medical devices such as catheters and perfusion tubing using relatively simple setups, they say there is a lot more on the horizon.

“We feel this is just the beginning of how we might test this for use in the clinic,” said co-lead author Daniel Leslie, Ph.D., a Wyss Institute Staff Scientist, who aims to test it on more complex systems such as dialysis machines and ECMO, a machine used in the intensive care unit to help critically ill patients breathe.

I first featured SLIPS technology in a Jan. 15, 2014 post about its possible use for stain-free, self-cleaning clothing. This Wyss Institute video about the latest work featuring the use of  SLIPS technology in medical devices also describes its possible use in pipelines and airplanes,

You can find research paper with this link,

A bioinspired omniphobic surface coating on medical devices prevents thrombosis and biofouling by Daniel C Leslie, Anna Waterhouse, Julia B Berthet, Thomas M Valentin, Alexander L Watters, Abhishek Jain, Philseok Kim, Benjamin D Hatton, Arthur Nedder, Kathryn Donovan, Elana H Super, Caitlin Howell, Christopher P Johnson, Thy L Vu, Dana E Bolgen, Sami Rifai, Anne R Hansen, Michael Aizenberg, Michael Super, Joanna Aizenberg, & Donald E Ingber. Nature Biotechnology (2014) doi:10.1038/nbt.3020 Published online 12 October 2014

This paper is behind a paywall but there is a free preview available via ReadCube Access.

Asthma on a chip

Harvard University’s Wyss Institute for Biologically Inspired Engineering has found a way to mimic the lung’s muscle action when an asthma attack is being experienced according to a Sept. 23, 2014 news item on Nanowerk,

The majority of drugs used to treat asthma today are the same ones that were used 50 years ago. New drugs are urgently needed to treat this chronic respiratory disease, which causes nearly 25 million people in the United States alone to wheeze, cough, and find it difficult at best to take a deep breath.

But finding new treatments is tough: asthma is a patient-specific disease, so what works for one person doesn’t necessarily work for another, and the animal models traditionally used to test new drug candidates often fail to mimic human responses–costing tremendous money and time.

Hope for healthier airways may be on the horizon thanks to a Harvard University team that has developed a human airway muscle-on-a-chip that could be used to test new drugs because it accurately mimics the way smooth muscle contracts in the human airway, under normal circumstances and when exposed to asthma triggers. [emphasis mine]

A Sept. 23, 2014 Wyss Institute news release (also on EurekAlert*), which originated the news item, provides more details about the technology and its advantages,

The chip, a soft polymer well that is mounted on a glass substrate, contains a planar array of microscale, engineered human airway muscles, designed to mimic the laminar structure of the muscular layers of the human airway.

To mimic a typical allergic asthma response, the team first introduced interleukin-13 (IL-13) to the chip. IL-13 is a natural protein often found in the airway of asthmatic patients that mediates the response of smooth muscle to an allergen.

Then they introduced acetylcholine, a neurotransmitter that causes smooth muscle to contract. Sure enough, the airway muscle on the chip hypercontracted – and the soft chip curled up – in response to higher doses of the neurotransmitter.

They achieved the reverse effect as well and triggered the muscle to relax using drugs called β-agonists, which are used in inhalers.

Significantly, they were able to measure the contractile stress of the muscle tissue as it responded to varying doses of the drugs, said lead author Alexander Peyton Nesmith, a Ph.D./M.D. student at Harvard SEAS and the University of Alabama at Birmingham. “Our chip offers a simple, reliable and direct way to measure human responses to an asthma trigger,” he said.

The team then investigated what happened on a cellular level in response to the IL-13 and confirmed, for example, that the smooth muscle cells grew larger in the presence of IL-13 over time – a structural hallmark of the airways in asthma patients as well. They also documented an increased alignment of actin fibers within smooth muscle cells, which is consistent with the muscle in the airway of asthma patients. Actin fibers are super-thin cellular components involved in muscle contraction.

Next they observed how IL-13 changes the expression of contractile proteins called RhoA proteins, which have been implicated in the asthmatic response, although the details of their activation and signaling have remained elusive. To do this they introduced a drug called HA1077, which is not currently used to treat asthmatic patients – but targets the RhoA pathway. It turns out that the drug made the asthmatic tissue on the chip less sensitive to the asthma trigger – and preliminary tests indicated that using a combined therapy of HA1077 plus a currently approved asthma drug worked better than the single drug alone.

“Asthma is one of the top reasons for trips to the emergency room – particularly for children, and a large segment of the asthmatic population doesn’t respond to currently available treatments,” said Wyss Institute Founding Director Don Ingber, M.D., Ph.D. “The airway muscle-on-a-chip provides an important and exciting new tool for discovering new therapeutic agents.”

The scientists have provided an illustration of healthy and asthmatic airways,

Schematic comparing a healthy airway (few immune cells, normal airway diameter) to an asthmatic airway (many immune cells, constricted airway). Credit: Harvard's Wyss Institute and Harvard SEAS [School of Engineering and Applied Sciences]

Schematic comparing a healthy airway (few immune cells, normal airway diameter) to an asthmatic airway (many immune cells, constricted airway). Credit: Harvard’s Wyss Institute and Harvard SEAS [School of Engineering and Applied Sciences]

Here’s link to and a citation for the paper,

Human airway musculature on a chip: an in vitro model of allergic asthmatic bronchoconstriction and bronchodilation by Alexander Peyton Nesmith, Ashutosh Agarwal, Megan Laura McCain and Kevin Kit Parker.Lab Chip, 2014,14, 3925-3936 DOI: 10.1039/C4LC00688G First published online 05 Aug 2014

This paper is open access provided you have registered yourself for free at the site.

* EurekAlert link added Sept. 24, 2014.